rs5030060

Positions:

• chr3-186735128-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001102416.3(KNG1):​c.930+2454C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 152,066 control chromosomes in the GnomAD database, including 5,213 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (5213 hom., cov: 32)
• Consequence: KNG1 NM_001102416.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.179

Genes affected

KNG1 (HGNC:6383): (kininogen 1) This gene uses alternative splicing to generate two different proteins- high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK). HMWK is essential for blood coagulation and assembly of the kallikrein-kinin system. Also, bradykinin, a peptide causing numerous physiological effects, is released from HMWK. Bradykinin also functions as an antimicrobial peptide with antibacterial and antifungal activity. In contrast to HMWK, LMWK is not involved in blood coagulation. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduces or depletes angiotensin converting enzyme 2 (ACE2), which results in an increase in levels of des-Arg(9)-bradykinin, a bioactive metabolite of bradykinin that is associated with lung injury and inflammation. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2020]

HRG-AS1 (HGNC:55915): (HRG and FETUB antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KNG1	NM_001102416.3	c.930+2454C>T		intron_variant		ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4	c.930+2454C>T		intron_variant			NP_000884.1
KNG1	NM_001166451.2	c.822+2454C>T		intron_variant			NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2	c.930+2454C>T		intron_variant			NM_001102416.3	ENSP00000493985
HRG-AS1	ENST00000630178.2	n.135+8575G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35600 AN: 151948 Hom.: 5209 Cov.: 32

Gnomad AFR AF: 0.0566

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.191

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.271

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.234 AC: 35613 AN: 152066 Hom.: 5213 Cov.: 32 AF XY: 0.235 AC XY: 17474 AN XY: 74334

Gnomad4 AFR AF: 0.0564

Gnomad4 AMR AF: 0.328

Gnomad4 ASJ AF: 0.348

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.284

Gnomad4 NFE AF: 0.312

Gnomad4 OTH AF: 0.271

Alfa AF: 0.304 Hom.: 14475

Bravo AF: 0.235

Asia WGS AF: 0.214 AC: 743 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.0
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5030060; hg19: chr3-186452917;